An arrhythmia is a disorder with the speed or rhythm of the heartbeat. Atrial fibrillation (AF) is the most common type of arrhythmia. The cause is a disorder in the heart's electrical system. Atrial fibrillation (AF) is a significant complication that occurs in about 30% of the patients undergoing cardiac surgery. The risk of AF increases with age. Patients over 30 years of age exhibit a 75% increase in AF for every decade of life. The molecular mechanism of acute AF following cardiac surgery is not well understood. Impaired hemodynamics, endothelial dysfunction, inflammation, oxidative stress, and thrombosis have been implicated as important contributors to AF. In AF patients, turbulent blood flow impacts nitric oxide (NO) bioavailability, producing vascular dysfunctions and activation of coagulation system which may contribute to the high rate of embolic events. Drugs that reduce vascular inflammation and improve vascular dysfunction and NO bioavailability may be efficacious for the prevention and treatment AF. One such class of drugs that exhibit these vascular and cardiac pleotropic effects are the HMG-COA inhibitors statins. It is widely documented that statins reduce vascular inflammation, oxidative stress and improve NO generation. Statins also modulate small GTPase including Rac1 by isoprenylation. Rac1 binds to p67phox and leads to activation of the NADPH oxidase system and subsequent generation of reactive oxygen species (ROS). Indeed, Rac1 activity is closely related to ROS production and ROS generated by NADPH oxidase in response to growth factors and inflammatory cytokines is mediated by Rac1. Importantly, statins inhibit Rac1-mediated NADPH oxidase activity and thereby reduce angiotensin II-induced ROS production and hypertrophy in smooth muscle and heart. Rac 1 has been shown to play role in the pathogenesis of AF. Transgenic mice overexpressing Rac1 exhibit conduction abnormalities and atrial fibrosis.
Observational and prospective studies have suggested beneficial effect of statin on AF (Liakopoulos O J et al. Euro. Heart J. 29; 1548-4559 (2008)) However, results of other prospective studies have been negative. For example, Collard, et al. (J. Thorac. Cardiovasc. Surg. 2006, 132:392) and Thielman, et al. (J. Thorac. Cardiovas. Surg. 2007; 134, 1143) failed to show decrease in all cause mortality in patients using statin before cardiac surgery.
There have been a limited number of trials on the effect of systemically administered statin on atrial fibrillation. The results are inconsistent and, in most cases, not statistically significant. For example, Negi, et al., J. Cardiovasc. Electrophysiol. April; 22(4):414-9 (2011) reported on a randomized, double-blinded, placebo-controlled trial, where patients with atrial fibrillation/flutter (AF) were randomized to receive either atorvastatin 80 mg (n=33) or placebo (n=31) before CV. Treatment was continued for 12 months or until AF recurred. They concluded that high-dose atorvastatin did not reduce the recurrence of AF after CV. It reduced selective markers of inflammation without affecting systemic oxidative stress. Failure of atorvastatin to prevent AF recurrence may be due to its failure to affect oxidative stress. Another study has shown that atorvastatin but not simvastatin was effective in prevention of AF (Naji et al Int. Heart J. 50, 153-160 (2009)). The inconsistent effect of statins could also be due to inadequate and inconsistent concentration at the target site when administered orally. Further limitations to the efficacy may be due to variability of patient's response to liver metabolism when delivered orally. The high dose of statins also increase the risk of liver and muscle toxicities. Alves, et al. Arg. Bras Cardiol. 2010 Sep. 24. pii: S0066-782X2010005000129. [Epub ahead of print] reported on a study to evaluate whether the chronic and regular use of statins, for a period of six months, prevents atrial fibrillation after elective cardiac surgery. In the postoperative period, atrial fibrillation was present in 42 patients (39%) of the sample, including 11 (26%) people that had used statins on a regular basis in the preoperative period and 31 (74%) who had not. They concluded that the regular use of statin, for six months or more in the preoperative period, reduced the incidence of atrial fibrillation after elective cardiac surgery. In a third report, Kinoshita, et al., Circ. J. 74(9):1846-51 (2010). Epub 2010 Jul. 6, reported on a study to assess the preventive effect of preoperative statin treatment on atrial fibrillation (AF) after elective isolated off-pump coronary artery bypass grafting (off-pump CABG) in propensity score-matched Japanese patients. 584 patients were retrospectively reviewed from among 770 consecutive patients undergoing isolated CABG by the same surgeon (99.2% with off-pump technique without conversion to cardiopulmonary bypass) between 2002 and 2009, after excluding emergency (n=150), chronic AF (n=30), and use of cardiopulmonary bypass (n=6). 364 patients received statin at least 5 days before operation and 220 patients received no statin. The concluded that preoperative statin significantly reduces the incidence of AF after elective isolated off-pump CABG in Japanese patients.
It is therefore an object of the present invention to provide a means for treating or preventing atrial fibrillation.